The peptide hormone relaxin was discovered in 1926 as a hormone of pregnancy, due to its effects to relax pubic ligaments and soften the cervix to facilitate parturition (Hisaw, F. L., Proc. Soc. Exp. Biol. Med. 1926, 23(8), 661-663; Fevold. H. L. et al., J. Am. Chem. Soc. 1930, 52(8), 3340-3348). Since then, it has been shown that blood concentrations of relaxin rise during the first trimester of pregnancy, promoting cardiovascular and renal adjustments to meet the increased nutritional demands of the growing fetus, and the elevated requirements for renal clearance of metabolic wastes (Baylis. C., Am. J. Kidney Dis. 1999, 34, 1142-4). Relaxin induces a 20% increase in cardiac output, 30% decrease in systemic vascular resistance, 30% increase in global arterial compliance, and 45% increase in renal blood flow during pregnancy (Schrier, R. W. et al., Am. J. Kidney Dis. 1987, 9, 284-9). Numerous clinical and nonclinical studies using this hormone have now recapitulated these cardiovascular effects in both males and females, demonstrating the pharmacological utility of relaxin in modulating cardiovascular and renal functions in humans.
The X-ray crystal structure of relaxin at 1.5 Å resolution was reported for the physiologically active form of the human hormone in 1991. The physiological effects of relaxin are mediated by its interaction with a G protein-coupled receptor (RXFP1) leading to the modulation of several signal transduction pathways. Activation of RXFP1 by relaxin induces: 1) up-regulation of the endothelin system which leads to vasodilation; 2) extracellular matrix remodeling through regulation of collagen deposition, cell invasiveness, proliferation, and overall tissue homeostasis; 3) a moderation of inflammation by reducing levels of inflammatory cytokines, such as TNF-α and TGF-β; and 4) angiogenesis by activating transcription of VEGF. The understanding of the biological effects of RXFP1 activation by relaxin has led to the evaluation of relaxin as a pharmacologic agent for the treatment of patients with acute heart failure (AHF), pre-eclampsia, and hypertensive disease. In addition, several clinical trials studied the therapeutic role of relaxin in treatment of scleroderma, cervical ripening, fibromyalgia, and orthodontics, given its function as anti-inflammatory and extracellular matrix remodeler.
The latest statistics indicate that 1 of every 2.9 deaths in the United States is due to cardiovascular disease (CVD) (Roger, V. L. et al., Circulation 2011, 123(4), 459-463). Each year, ˜795,000 people experience a new or recurrent stroke, and 1 in 9 death certificates in the United States mention heart failure. In addition, 33.5% of US adults over 20 years of age have hypertension. These statistics clearly illustrate the limitations of current therapies to address CVD in general and acute heart failure (AHF) in particular. The significant contribution of vascular dysfunction to the pathophysiology of AHF has more recently been recognized. These patients are characterized by preserved or elevated systolic blood pressure and increased vascular stiffness with less fluid overload. They are more likely to be elderly and female. Large-scale registry studies suggest that patients with vascular dysfunction causing AHF represent the majority of patients, and that this may have been underappreciated during previous development of new therapies.
Therapeutically, there is a great medical need for better approaches to treat heart failure. Currently, there are two major methodologies: a) surgery and medical devices: coronary bypass surgery, heart valve repair or replacement, implantable cardioverter-defibrillators (ICDs), heart pumps (left ventricular assist devices, or LVADs), or heart transplant; b) medications: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), digoxin (lanoxin), beta blockers and aldosterone antagonists. Importantly, none of these approaches are able to address the development of scar heart tissue after severe heart failure, or repair it after damage. In that sense the anti-fibrotic and remodeling properties of relaxin, together with its capacity to normalize blood pressure, increase blood and renal flow, while it promotes decongestion and vascular compliance, seem to be ideal for treating these conditions. Clinical data agrees with this theory (Teichman S. L. et al, Curr. Heart Failure Rep. 2010, 7, 75-82). Relaxin relieves systemic and renal vasoconstriction and increases vascular compliance, including normalization of high blood pressure, reduction of pulmonary capillary wedge pressure, increase of cardiac output, increase renal blood flow, natriuresis, and decongestion. In addition, animal pharmacology data indicate that relaxin hormone has anti-inflammatory and cardiac protection effects, including reduction of myocardial ischemia, reduction of reperfusion injury, increase of wound healing, and reduction of ventricular fibrosis.
Recombinant relaxin hormone has produced excellent responses in clinical trials for treatment of heart failure and is about to reach commercialization. However, administration of the peptide is difficult in chronic settings. In view of the foregoing, there is an unmet need for new small molecule agonists of the RXFP1 receptor.